Uses of adenosine base editors

US11795443B2 · kind B2 · utility

Assignees

• The Broad Institute, Inc. · US
• President and Fellows of Harvard College · US
• Beam Therapeutics Inc. · US

Inventors

• David R. Liu · Lexington, US
• Nicole Gaudelli · Cambridge, US
• Michael S. Packer · Cambridge, US
• Gregory Newby · Cambridge, US

Key dates

• Filing date: Oct 16, 2018
• Grant date: Oct 24, 2023
• Expiry date: Apr 13, 2039

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12N2800/80
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The disclosure provides methods and compositions for treating blood diseases/disorders, such as sickle cell disease, hemochromatosis, hemophilia, and beta-thalassemia. For example the disclosure provides therapeutic guide RNAs that target the promotor of HBG1/2 to generate point mutations that increase expression of fetal hemoglobin. As another example, the disclosure provides therapeutic guide RNAs that target mutations in HBB, Factor VIII, and HFE to treat sickle cell disease, beta-thalassemia, hemophilia and hemochromatosis. The disclosure also provides fusion proteins comprising a Cas9 (e.g., a Cas9 nickase) domain and adenosine deaminases that deaminate adenosine in DNA. In some embodiments, the fusion proteins are in complex with nucleic acids, such as guide RNAs (gRNAs), which target the fusion proteins to a DNA sequence (e.g., an HBG1 or HBG2 protmoter sequence, or an HFE, GBB, or F8 gene sequence). Such complexes may be useful for increasing expression of fetal hemoglobin or correcting a poing mutation (e.g., C282Y) in HFE.